PROJECT SUMMARY Cardiovascular disease (CVD) continues to be the leading cause of death in the United States. As the prevalence of CVD increases amongst our aging population, the already high cost of treating CVD in the United States is expected to grow significantly over the next few decades. Certain populations such as HIV-infected individuals have an increased risk of cardiovascular disease. Indeed, HIV- infected individuals have a 50% increased risk of myocardial infarction as compared to non-HIV- infected individuals, even after controlling for traditional CVD risk factors. Atherosclerotic plaque formation is a highly inflammatory process that is characterized by infiltration of activated macrophages within the blood vessel wall. Given that the atherosclerotic plaques that are most vulnerable to rupture are thin-cap fibrous atheromatous plaques which are highly infiltrated with macrophages, the identification of individuals with macrophage-specific arterial inflammation could be used to identify HIV-infected individuals at highest risk of a myocardial infarction. In this cross- sectional study, 40 subjects will be enrolled into four different groups: HIV-infected subjects with subclinical atherosclerosis, non-HIV-infected subjects with subclinical atherosclerosis, HIV-infected subjects without subclinical atherosclerosis, and non-HIV-infected subjects without subclinical atherosclerosis. Subjects in these four groups will undergo a focused set of cardiovascular imaging assessments, including coronary computed tomography angiography (CCTA) and novel 99mtechnetium -tilmanocept Single-Photon Emission Computed Tomography-CT (99mTc-tilmanocept SPECT/CT). The primary aim of this study will be to determine the independent effects of HIV status and atherosclerotic plaque on arterial macrophage infiltration assessed using 99mTc-tilmanocept SPECT/CT among all four groups. Detailed immune phenotyping (using flow cytometry and measurement of markers of systemic immune activation and arterial inflammation) will be correlated with the degree of arterial inflammation, to identify specific immune/inflammatory pathways contributing to the immunopathology of HIV- associated CVD. Taken together, this study will lead to the development of a novel non-invasive cardiovascular molecular imaging modality that can be used to assess macrophage-specific arterial inflammation in HIV and in the future can be used to identify HIV-infected individuals at high risk for CVD events. Moreover, the elucidation of specific immune pathways that are associated with this macrophage-specific inflammation can help guide targeted therapies for the treatment and prevention of atherogenesis in HIV; thereby significantly impacting the field of HIV cardiovascular medicine.